Antibody-mediated enhancement of Flavivirus replication in macrophage-like cell lines

Abstract

Interactions between animal viruses and antiviral antisera may exceptionally result in an apparent increase in viral infectivity. Halstead and coworkers demonstrated enhanced replication of dengue virus (a Flavivirus, family Togaviridae) in human or simian peripheral blood leucocytes carrying Fc receptors at subneutralising concentrations of antidengue antibody. We have used three continuous cell lines which express macrophage markers to explore the mechanism of this phenomenon. Dengue virus failed to replicate in these cells, but West Nile virus, another Flavivirus, replicated in all three, and we were able to demonstrate reproducibly 50--100-fold enhancement of virus yields in the presence of Flavivirus antisera, the effect also being directly demonstrable in P388D1 cells by increased numbers of virus-induced plaques. The phenomenon of antibody-dependent enhancement of viral replication is not unique to dengue virus, and may have far wider relevance in other viral infections.

Molecular mechanism of pathogenesis of dengue virus: Entry and fusion with target cell

“…Penetration is pHdependent with the threshold for fusion being at about pH 6.5. The mechanism of entry into macrophages is of particular interest, as it is mediated by antibodies and presumably occurs via Fc receptors (Gollins and Porterfield, 1985;Peiris and Porterfield, 1979;Peiris et al, 1981). Gollins and Porterfield (1986) have made an important observation that has implications for therapeutic strategies against flaviviruses.…”

Immunological enhancement and the pathogenesis of dengue haemorrhagic fever

“…Sundstrom & Wunderlich, 1975Cohn, 1975Van Loveren et al 1981Nilsson, 1976 Using P388D1 cells, were able to demonstrate antibody dependent plaque enhancement with six flaviviruses, (two strains of West Nile, Kunjin, Murray Valley encephalitis and Uganda S viruses), three alphaviruses, (Semliki Forest, Sindbis and Western Equine encephalitis viruses), three Bunyaviridae, (Bunyamwera, Lokern and Trivittatus viruses), but were unable to show enhancement with Herpes simplex virus (family Herpesviridae) or with Mengo virus (family Picornaviridae). Although negative results were initially reported (Peiris & Porterfield, 1979) more recent tests with dengue virus, using the 16681 strain, have succeeded in demonstrating enhancement, although without any cytopathic effect. ).…”

“…Two macrophage cell lines of mouse origin, P388D1 and J774. 1, and the U937 line of human origin, were tested by Peiris & Porterfield (1979); they failed to detect replication of dengue virus in these cells, but were able to show that another flavivirus, West Nile virus (WNV), did replicate in all three cell lines, and that virus yields were enhanced in all three lines by appropriate concentrations of antiviral antibody. Enhancement could be detected by a two stage assay, using plaque formation in the PS line of pig kidney cells to titrate the yields of WNV produced in macrophages infected either with or without antiviral antibody.…”

“…Alternatively the PS cells could be used to measure the number of infectious centres induced in macrophages infected under the different conditions. However, a direct assay of antibody dependent plaque enhancement (ADPE) was possible in one of the mouse macrophage cell lines, since lytic plaques formed in P388D1 monolayers when these were incubated under carboxymethyl cellulose overlays (Peiris & Porterfield, 1979, 1981. This direct ADPE assay was not possible with either the J774.1 or U937 cells, since these attach very poorly to glass or plastic surfaces.…”

“…Enhanced replication in the presence of antiviral antibody has been reported to occur in U937 cells with three different flaviviruses, West Nile virus, (Peiris & Porterfield, 1979), yellow fever virus, (Schlesinger & Brandriss, 1981), and dengue virus, . The magnitude of the West Nile virus enhancement was similar to that observed in P388D1 cells, and since the latter cells permitted a direct estimate of enhancement by counting plaque numbers, Peiris & Porterfield (1979, 1981 did most of their work on P388D1 cells.…”